Anti-Inflammatory Effects of Epoxyeicosatrienoic Acids

Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
International journal of vascular medicine 07/2012; 2012(1):605101. DOI: 10.1155/2012/605101
Source: PubMed


Epoxyeicosatrienoic acids (EETs) are generated by the activity of both selective and also more general cytochrome p450 (CYP) enzymes on arachidonic acid and inactivated largely by soluble epoxide hydrolase (sEH), which converts them to their corresponding dihydroxyeicosatrienoic acids (DHETs). EETs have been shown to have a diverse range of effects on the vasculature including relaxation of vascular tone, cellular proliferation, and angiogenesis as well as the migration of smooth muscle cells. This paper will highlight the growing evidence that EETs also mediate a number of anti-inflammatory effects in the cardiovascular system. In particular, numerous studies have demonstrated that potentiation of EET activity using different methods can inhibit inflammatory gene expression and signalling pathways in endothelial cells and monocytes and in models of cardiovascular diseases. The mechanisms by which EETs mediate their effects are largely unknown but may include direct binding to peroxisome proliferator-activated receptors (PPARs), G-protein coupled receptors (GPCRs), or transient receptor potential (TRP) channels, which initiate anti-inflammatory signalling cascades.

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    • "Although the existence and biological relevance of prostaglandins have been known for over half a century , the contribution of EETs to the regulation of these processes has only been realized within the past two decades (Morisseau and Hammock, 2013). Compared to the pro-inflammatory prostaglandins, EETs are potently anti-inflammatory (Thomson et al., 2012), antihypertensive (Jiang et al., 2011), anticonvulsive (Inceoglu et al., 2013) and analgesic (Inceoglu et al., 2008; Inceoglu et al., 2006). Concentrations of EETs are reported to be regulated both by their synthesis by P450s, particularly −2J2 and −2C8 in addition to others, and by their hydrolysis by sEH (Chacos et al., 1983; Imig, 2012; Morisseau and Hammock, 2013). "
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    ABSTRACT: Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7days)+TPPU (3mg/kg/day, p.o., last 3days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.
    Toxicology and Applied Pharmacology 11/2015; DOI:10.1016/j.taap.2015.10.018 · 3.71 Impact Factor
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    • "Despite the use of enabling formulations, increases in exposure following oral delivery are often not achieved. IT has been studied that (EETs) can affect vasodilatation and vasoconstriction in several vascular beds [1] [2] [3] [4]. According to their research, anti-inflammatory, anti-hypertensive, and other therapeutic benefitscan be achieved with increasing the levels of EETs [5] [6] [7] [8] [9] [10] [11]. "
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    ABSTRACT: Hypertension is a common medical condition in the general population. Researchers are constantly looking for new medications to control this disease. Recently, soluble epoxide hydrolase (sEH) was identified as possible new drug target for hypertension. 1, 3-dicyclohexylurea (1,3-DCU) was reported to inhibit the sEH at nM range. However, due to the poor oral bioavailability (BA) of 1,3-DCU (even at low dose), utilizing1,3 –DCU in this target research become problematic. It is believed that the key ADME issues of 1,3-DCU are poor aqueous solubility, poor dissolution rate, and high systemic clearance. Formerly, ananosuspension/crystalline nanoparticle formulation has been used in the rats and observed higherBA. Despite the improvement, the mechanism ofhow crystalline nanoparticleimproves the BA has not been fully understood. The prediction of howcrystalline nanoparticleperforms in vivoremains uncertain. Therefore, a tool needs to be developed to better understand the enhanced BA of 1,3-DCUcrystalline nanoparticle. In this study, the limitation of the oral delivery of 1, 3-DCU was assessed by a dynamic model combines measured intrinsic dissolution rate, particle size, gastrointestinal transit (GI), and diffusion through unstirred water layer to estimate the amount of drug absorbed and then followed by multi-compartmental pharmacokinetic analysis. It was found that this modeling approach adequately captures the effect of a crystalline nanoparticle formulation and mimicking the oral BA. The ultimate goal for this study is to assess the suitability of using a new dynamic modeling approach to predict in vivo performance of the crystalline nanoparticle. This work may aid in future investigations of similar compounds.
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    • "P450s also mediate one of the three major pathways of arachidonic acid (AA) metabolism, producing hydroxyeicosatrienoic acids (HETES) and epoxyeicosatrienoic acids (EETs). EETs, which are readily converted to dihydroxyeicosatrienoic acids (DiHETEs) by epoxide hydrolases, are well-known anti-inflammatory mediators262728. In in vitro studies, we detected a number of AA metabolites in small intestinal microsomal reactions with AA, including 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, 5,6-DiHETE, 8,9-DiHETE, 11,12-DiHETE,14,15-DiHETE, 19-HETE and 20-HETE, of which 11,12-DiHETE and 14,15-DiHETE appeared to be the most abundant (data not shown); the rates of metabolite formation were substantially lower in IE-Cpr-null mice than in WT mice, thus confirming role of microsomal P450 enzymes in intestinal AA metabolism. "
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    ABSTRACT: Cytochrome P450 (P450) enzymes are a superfamily of heme-containing enzymes involved in the metabolism of various endogenous compounds, including retinoids, glucocorticoids, and eicosanoids, that are postulated to participate in the maintenance and/or development of inflammatory and immune reactions in the intestinal mucosa. To investigate the role of P450 enzymes in intestinal inflammation and immunity, we took advantage of IE-Cpr-null mice, which are deficient in intestinal epithelium of NADPH-cytochrome P450 reductase (CPR), the obligate redox partner of all microsomal P450 enzymes. We report that IE-Cpr-null mice, following an acute toxin challenge, had higher levels of pro-inflammatory chemokines and increased tissue damage compared to wild-type mice. IE-Cpr-null mice had normal Peyer's patch numbers and elicited normal secretory IgA (SIgA) responses. However, SIgA baseline levels in IE-Cpr-null mice were consistently elevated over WT littermates. While neither retinoic acid nor glucocorticoid levels in serum and intestinal homogenates were altered in IE-Cpr-null mice, basal levels of arachidonic acid metabolites (11,12-DiHETE and 14,15-DiHETE) with known anti-inflammatory property were significantly lower compared to WT controls. Overall, these findings reveal immunological and metabolic changes resulting from a genetic deficiency in CPR expression in the intestine, and support a role for microsomal P450 enzymes in mucosal homeostasis and immunity.
    Scientific Reports 07/2014; 4:5551. DOI:10.1038/srep05551 · 5.58 Impact Factor
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